Epothilone derivatives, a process for their production thereof and their use

ABSTRACT

The present invention relates to epothilon derivatives, processes for their production and their use in the manufacture of medicaments and plant protection agents.

[0001] The present invention relates generally to epothilon derivatives, to processes for their production and to their use in the manufacture of medicaments and plant protection agents. The invention relates especially to epothilon derivatives of the general formulae 2 to 6 shown below and to their use as medicaments and plant protection agents.

[0002] In the above formulae:

[0003] R¹=a H atom or a C₁- to C₈-alkyl group, preferably a C₁- to C₆-alkyl group, especially preferably a C₁- to C₄-alkyl group, especially a methyl, ethyl, propyl or butyl group,

[0004] R²=a monocyclic aromatic group, such as a 5- or 6-membered aromatic group (such as a phenyl ring) or a vinyl group, each of which may be substituted in the ortho- and/or meta- and/or para-position(s) by one, two, three, four or five, especially one or two, halogen atoms and/or OR⁴ and/or NR⁵R⁶ groups and/or alkyl and/or alkenyl and/or alkynyl groups, wherein R⁴, R⁵ and R⁶ each independently of the others have the same meanings as R¹, but are independent of R¹, or

[0005] R²=a monocyclic 5- or 6-membered heteroaromatic group which may have one or more, especially one or two, O and/or N and/or S atoms in the ring and/or may have OR⁴ and/or NR⁵R⁶ groups and/or alkyl and/or alkenyl and/or alkynyl groups as substituents, wherein R⁴, R⁵ and R⁶ are as defined above. In the definition of R² there are especially preferred C₁-C₆-alkyl or C₂-C₆-alkenyl and -alkynyl groups, especially C₁-C₄-alkyl or C₂-C₄-alkenyl and -alkynyl groups. As alkyl groups there are especially preferred methyl, ethyl, propyl and butyl groups and as heteroaromatic groups 6-membered heteroaromatic groups,

[0006] Hal=a halogen atom, such as Br or I,

[0007] X-Y=a group of the formula —CH₂CH—OP or —CH═CH—, and

[0008] P=a protecting group, such as TMS.

[0009] The compounds according to the invention may be produced as follows:

[0010] Compounds of the formula (2) may be produced by reacting compounds of the formula (1)

[0011] as described in DE 195 42 986, the radicals being as defined above. In that reaction, especially the following conditions (i), (iii) and optionally (after (i)) also (ii) may be used:

[0012] (i)

[0013] (a) O₃ in a solvent, such as CH₂Cl₂, and

[0014] (b) reductive working-up, for example with Me₂S;

[0015] (ii)

[0016] (a) (CH₃CO)₂O, HCO₂H, NEt₃, DMAP;

[0017] (b) DBU; and

[0018] (c) MeOH, NH₃; and

[0019] (iii) Me₃SiCl, NEt₃.

[0020] Compounds of the formula (3) are obtainable by reacting a compound of the formula (2) with a compound of the formula HC[B(OR)₂]₃, such as tris(ethylenedioxyboryl)methane; R may be an alkyl or alkenyl group as defined above.

[0021] In the reaction there is optionally used a strong base, such as a C₁-C₄-alkyl-Li compound (such as butyllithium) or a di-C₁-C₄-alkylamine-Li compound (such as a dimethylamine-lithium compound). The reaction is generally carried out at low temperatures, such as, for example, at temperatures of less than −30° C., preferably at temperatures of less than −50° C., especially preferably at temperatures of at least −78° C. Further reaction conditions may be found in D. Schummer, G. Höfle in Tetrahedron 1995, 51, 11219.

[0022] For example, a compound of the formula (2) is reacted with tris(ethylenedioxyboryl)methane and butyllithium at −78° C. to form a compound of the formula (3).

[0023] A compound of the formula (4) may be produced from a compound of the formula (3) by reaction with N-iodo- or N-bromo-succinimide, optionally in a polar solvent, such as acetonitrile. Further reaction conditions may be found in the following literature reference: N. A. Petasis, I. A. Zavialor, Tetrahedron Lett. 1996, 37, 567.

[0024] For the production of a compound of the formula (5), a compound of the formula (3) may be reacted within the framework of a Suzuki coupling with a compound of the formula R²-Z, wherein R² has the meanings given above and Z may be a halogen atom or a group of the formula —OSO₂CF₃, —CH═CHI, —CH═CHOSO₂CF₃. The group R²-Z may especially have the following structures:

[0025] wherein A¹ represents O, S, N or C atoms and the substituents O—, N— and C— correspond to the above-described groups OR⁴, NR⁵R⁶ and alkyl, alkenyl and/or alkynyl groups.

[0026] Especially preferred as substituents “C” are C₁-C₆-alkyl or C₂-C₆-alkenyl and/or -alkynyl groups, especially C₁-C₄-alkyl or C₂-C₄-alkenyl and/or -alkynyl groups. As alkyl groups there are especially preferred methyl, ethyl, propyl and butyl groups.

[0027] Alternatively, a compound of the formula (5) may be produced by reacting a compound of the formula (4) by means of a Stille coupling with R²—SnR³ ₃, wherein R² is as defined above and R³ is a C₁- to C₆-alkyl group, preferably a C₁- to C₄-alkyl group and especially preferably a methyl, ethyl, propyl or butyl group. In addition, the compound R²—SnR³ ₃ may have one of the following structures:

[0028] wherein the radicals and substituents are as defined above.

[0029] Furthermore, according to the invention, a compound of the formula (6) may be produced by removing the protecting group from the compound of the formula (5), for example with a weak acid, such as citric acid, or compounds such as TBAF, pyridine×HF. Optionally an alcohol, such as methanol, may be used as solvent, the temperature preferably being adjusted to values of, for example, from 40 to 60° C., preferably about 50° C.

[0030] In summary, the compound of the formula (6) may be produced by the above-described steps (epothilon A or B→(2)→(3)→(4)→(5)→(6) or epothilon A or B→(2)→(3)→(5)→(6)).

[0031] According to the invention there are also disclosed medicaments that contain at least one of the compounds (2), (3), (4), (5) or (6) and optionally customary carriers, diluents and adjuvants.

[0032] Such compounds may especially be used also as cytostatic agents and for plant protection in agriculture and/or forestry and/or in horticulture, the compounds optionally being used together with one or more customary carriers, adjuvants and/or diluents.

EXAMPLES

[0033] Synthesis of the Ketone Derivatives 2

[0034] For a detailed description see DE 195 42 986 A1.

[0035] Synthesis of the Alkenylboronic Acid Derivatives 3

[0036] (see also D. Schummer, G. Höfle, Tetrahedron 1995, 51, 11219)

[0037] Typical Example (R¹=H, X-Y=CH₂CHOTMS):

[0038] A solution of tris(ethylenedioxyboryl)methane (0.30 g, 1.5 mmol) in CH₂Cl₂/THF (1:1; 4 ml) was prepared and cooled under inert gas to −78° C. At that temperature, butyllithium (1.6M solution in hexane; 0.73 ml, 1.2 mmol) was added drop-wise in the course of 10 minutes. After 2 hours, ketone 2 (81 mg, 0.15 mmol) in CH₂Cl₂/THF (1:1, 2 ml) was added, heated to room temperature and stirred for 17 hours. After the addition of MeOH (2 ml), the clear reaction solution was purified by means of preparative HPLC (Lichroprep RP-18, CH₃CN/H₂O 75:25). 57 mg (65%) of alkenylboronic acid 3 were obtained in the form of an E/Z-isomeric mixture (6:4).

[0039] Selected typical data: LC-MS (ESI-MS): 585 (M⁺+H); ¹H-NMR: (300 MHz, CD₃OD): E-isomer: 1.91 (S, 3H), 5.16 (d, 1H, 10 Hz), 5.49 (s, 1H), Z-isomer; 1.85 (d, 3H, 1.1 Hz), 4.93 (s, 1H), 5.26 (d, 1H, 9.6 Hz).

[0040] Synthesis of the Iodovinyl Derivatives 4

[0041] (see also N. A. Petasis, I. A. Zavialor, Tetrahedron Lett. 1996, 37, 567)

[0042] Typical Example (R¹=H, X-Y=CH₂CHOTMS):

[0043] At room temperature, N-iodosuccinimide (6.0 mg, 27 μmol) was added under inert gas and with the exclusion of light to a solution of alkenylboronic acid 3 (12 mg, 21 μmol; E/Z 9:1) in CH₃CN (150 μl) and stirred for 3 hours. After concentration, the residue was purified by means of preparative thin-layer chromatography (SiO₂, CH₂Cl₂/MeOH 95:5). 9 mg (66%) of the iodovinyl derivative 4 were isolated in the form of an E/Z-isomeric mixture (9:1).

[0044] Selected typical data: LC-MS (ESI-MS): 667 (M⁺+H); ¹H-NMR: (300 MHz, CDCl₃); E-isomer: 1.82 (d, 3H, 1.1 Hz), 5.36 (d, 1H, 11 Hz), 6.43 (s, 1H), Z-isomer: 1.84 (d, 3H, 1.1 Hz), 5.54 (d, 1H, 10.5 Hz), 6.09 (s, 1H).

[0045] Suzuki Coupling of the Alkenylboronic Acid 3

[0046] (see also A. Suzuki, Acc. Chem. Res. 1982, 15, 178; A. Torrado, S. Lopez, R. Alvarez, A. R. De Lera Synthesis, 1995, 285)

[0047] Typical Example (R¹=H, X-Y=CH₂CHOTMS, R²=Ph):

[0048] A solution of alkenylboronic acid 3 (12 mg, 21 μmol; E/Z 2:8) and thallium ethanolate (2M solution in EtOH; 12 μl, 24 μmol) in THF (150 μl) was stirred at room temperature for 15 minutes, then a solution of phenyl iodide (4.0 μl, 6.0 mg, 29 μmol) and tetrakis(triphenylphosphino)-palladium (7.1 mg, 6.2 μmol) in THF (150 μl) was added drop-wise in 30 minutes and again stirred for 30 minutes. After purification by means of preparative thin-layer chromatography (SiO₂, CH₂Cl₂/Et₂O 95:5) the phenyl-analogous epothilon 5 (10 mg, 79%, E/Z 2:8) was obtained in the form of a colourless solid.

[0049] Selected typical data: LC-MS (ESI-MS): 617 (M⁺+H); ¹H-NMR: (300 MHz, CDCl₃): E-isomer: 1.87 (d, 3H, 1.4 Hz), 5.35 (d, 1H, 10.7 Hz), 6.54 (s, 1H), Z-isomer: 1.80 (d, 3H, 1.5 Hz), 5.61 (d, 1H, 10.2 Hz), 6.41 (s, 1H).

[0050] Stille Coupling of the Iodovinyl Derivatives 4

[0051] (see also K. C. Nicolaou, Y. He, F. Roschangar, N. P. King, D. Vourloumis, T. Li Angew. Chem. 1998, 110, (1/2), 89) 

1-17. (cancelled)
 18. A compound of formula:

wherein R¹ is a H atom or a C₁- to C₈-alkyl group, X-Y is a group of the formula —CH₂CH(OP)— or —CH═CH—, P is a protecting group, and each R is independently a C₁- to C₈-alkyl group or a C₂- to C₆-alkenyl group.
 19. The compound of claim 18 wherein at least one R is a C₁- to C₆-alkyl group.
 20. The compound of claim 18 wherein at least one R is a C₁- to C₄-alkyl group.
 21. The compound of claim 18 wherein at least one R is a C₂- to C₆-alkenyl group.
 22. The compound of claim 18 wherein at least one R is a C₂- to C₄-alkenyl group.
 23. The compound of claim 18 wherein R¹ is a H atom or a C₁- to C₆-alkyl group.
 24. The compound of claim 18 wherein R¹ is a H atom or a methyl group.
 25. A process for preparing a compound of the formula

wherein R¹ is a H atom or a C₁- to C₈-alkyl group, X-Y is a group of the formula —CH₂CH(OP)— or —CH═CH—, P is a protecting group, and each R is independently a C₁- to C₈-alkyl group or a C₂- to C₆-alkenyl group; comprising: reacting a compound of the formula 2:

with a compound of the formula HC[B(OR)₂]₃.
 26. The process according to claim 25 wherein the compound of the formula HC[B(OR)₂]₃ is tris(ethylenedioxyboryl)methane.
 27. The process according to claim 25 wherein the compound of the formula 2 and the compound of the formula HC[B(OR)₂]₃ are reacted in the presence of a strong base.
 28. The process according to claim 27 wherein the strong base is a C₁-C₄-alkyl lithium compound or a di-C₁-C₄-alkylamine lithium compound.
 29. The process according to claim 28 wherein the strong base is butyllithium or dimethylamine lithium compound.
 30. The process according to claim 25 wherein the compound of the formula II and the compound of the formula HC[B(OR)₂]₃ are reacted at a temperature of less than about −30° C. 